Phaeochromocytoma and Paraganglioma
Summary
Phaeochromocytomas are rare catecholamine-secreting neuroendocrine tumours arising from chromaffin cells of the adrenal medulla. Related tumours arising from extra-adrenal sympathetic or parasympathetic ganglia are termed Paragangliomas. They classically present with paroxysmal "spells" of hypertension, headache, sweating, and palpitations. While historically described by the "Rule of 10s," modern genetics reveals that up to 30-40% are familial (associated with MEN2, VHL, NF1, SDH mutations). Diagnosis relies on biochemical demonstration of excess Metanephrines (catecholamine metabolites). Management is surgical, but crucial preoperative preparation with Alpha-blockade followed by Beta-blockade is mandatory to prevent lethal intraoperative hypertensive crises. [1,2]
Key Facts
- Terminology: Phaeochromocytoma = Intra-adrenal. Paraganglioma = Extra-adrenal (e.g., Organ of Zuckerkandl, Carotid Body).
- The "Rule of 10s" (Historical vs Modern):
- 10% Bilateral (True for sporadic, but 50% in MEN2/VHL).
- 10% Extra-adrenal.
- 10% Malignant (Higher for Paragangliomas and SDHB mutations).
- 10% Familial (FALSE: Modern data suggests ~30-40%).
- Clinical Triad: Headache + Palpitations + Sweating.
- Biochemistry: Measure Metanephrines (Plasma or Urine), NOT parent catecholamines (too unstable/intermittent).
- The Golden Rule: Alpha-blockade BEFORE Beta-blockade.
Clinical Pearls
"Unopposed Alpha Stimulation": If you give a Beta-blocker first, you block vasodilation (Beta-2) and heart rate (Beta-1). The circulating adrenaline now hits ONLY the Alpha-receptors (vasoconstriction). This causes a catastrophic spike in Blood Pressure. Never give a beta-blocker to a phaeo patient until alpha-blockade is established.
The "Paradoxical Response": In undiagnosed phaeo, giving certain drugs (Metoclopramide, Glucagon, Anaesthetic induction agents) can trigger a crisis.
Neurofibromatosis: Look for café-au-lait spots. 1-5% of NF1 patients have a phaeo.
Postural Hypotension: Despite having high BP, these patients are profoundly dry (volume contracted) due to vasoconstriction. When they stand, they drop their BP. High salt intake during pre-op prep is crucial to "refill the tank".
Incidence
- Rare: less than 0.2% of hypertensive population.
- Age: Peak 30-50 years (sporadic). Childhood (familial).
Genetic Associations (30-40%)
- MEN 2 (A and B): RET mutation. Bilateral phaeos common.
- Von Hippel-Lindau (VHL): VHL mutation.
- Neurofibromatosis Type 1 (NF1): NF1 mutation.
- Familial Paraganglioma: SDH (Succinate Dehydrogenase) mutations. SDHB is associated with malignancy.
Catecholamine Excess
- Tumours secrete Noradrenaline (predominant), Adrenaline, or rarely Dopamine.
- Alpha-1 Effect: Intense vasoconstriction → Hypertension, Pallor.
- Beta-1 Effect: Tachycardia, palpitations, increased contractility.
- Metabolism: Catecholamines are metabolised by COMT within the tumour to Metanephrines (Metanephrine/Normetanephrine). These leak continuously into plasma, making them better markers than intermittent catecholamines.
"The Great Mimic"
Symptoms are often paroxysmal ("Spells") lasting minutes to hours, triggered by stress, exercise, or abdominal pressure.
Red Flags (Crisis)
- BP: Check lying and standing. Postural drop is classic.
- Skin: Café-au-lait spots (NF1), neurofibromas.
- Eyes: Hypertensive retinopathy.
- Abdomen: Mass (rare). DO NOT PALPATE VIGOROUSLY (can release catecholamines).
Biochemical Screening (First line)
Medications interfering: Tricyclics, Phenoxybenzamine, L-Dopa can cause false positives.
- Plasma Free Metanephrines: High sensitivity. The test of choice.
- Patient should be lying supine for 20 mins before draw.
- 24-hour Urinary Metanephrines: Alternative.
Imaging (Localisation)
Only AFTER biochemical confirmation.
- CT Abdomen/Pelvis: High sensitivity (90-100%). Usually finds adrenal mass.
- MRI Abdomen: Preferred in children/pregnancy (no radiation). "Lightbulb sign" on T2 (bright).
- Functional Imaging:
- MIBG Scan (Metaiodobenzylguanidine): Analogue of uptake precursor. Specific for phaeo.
- PET-CT (Gallium-DOTATATE): High sensitivity, especially for metastases.
Genetic Testing
- Recommended for ALL patients with phaeochromocytoma (due to high heritability).
Management Algorithm
DIAGNOSIS CONFIRMED
(High Metanephrines)
↓
┌─────────────────────────────────────────────┐
│ PRE-OP PREPARATION (10-14 Days) │
│ 1. Alpha-Blockade (Phenoxybenzamine) │
│ - Start low (10mg BD) │
│ - High Salt Diet + Fluids │
│ 2. Beta-Blockade (Propranolol) │
│ - ADD ONLY once BP controlled / Tachy │
└─────────────────────────────────────────────┘
↓
SURGICAL RESECTION
(Adrenalectomy)
- Laparoscopic preferred
- "No touch" technique
↓
POST-OP MONITORING
- Watch for HYPOtension
- Check Glucose (hypoglycaemia)
1. Medical Preparation (Mandatory)
- Phenoxybenzamine: Non-selective, irreversible alpha-blocker.
- Start 10-14 days pre-op.
- Aim: BP less than 130/80 (seated) and less than 90 systolic (standing). Nasal stuffiness is a sign of effective blockade.
- Side effects: Orthostatic hypotension, tachycardia.
- Doxazosin: Selective alpha-1 blocker. Alternative (fewer side effects, but arguably less complete blockade).
- Beta-Blockers: Propranolol or Atenolol.
- Added 2-3 days after alpha-blockade to control reflex tachycardia.
- Volume Expansion: High salt diet and IV fluids to restore plasma volume before surgery.
2. Surgery
- Laparoscopic Adrenalectomy: Gold standard.
- Partial (Cortical-sparing): Considered in hereditary bilateral disease to preserve cortisol function.
- Anaesthesia: Deep anaesthesia, invasive monitoring (Arterial line). Avoid histamine-releasing drugs. Phentolamine/SNP on standby for crisis.
3. Acute Crisis Management
- Phentolamine (IV Alpha-blocker): Titratable short-acting.
- Sodium Nitroprusside: Vasodilator.
- Labetalol: Combined alpha/beta (IV). Use with caution.
- Hypertensive Crisis: Stroke, Arrhythmia, MI.
- Post-operative Hypotension: Sudden drop in catecholamines + residual alpha-blockade. Requires aggressive fluid resuscitation/vasopressors.
- Post-operative Hypoglycaemia: Refund of insulin sensitivity.
- Malignancy (Metastasis): Bones, Liver, Lungs. 5-year survival ~50%.
- Benign: Cure with surgery. Hypertension resolves in 75%.
- Recurrence: Long-term follow-up required (annual metanephrines), especially for familial cases.
Key Guidelines
| Guideline | Organisation | Key Recommendations |
|---|---|---|
| Phaeochromocytoma Management | Endocrine Society (2014) | Biochemical testing first. Alpha-blockade 7-14 days pre-op. |
| Genetic Screening | European Society of Endocrinology | Offer genetic testing to ALL patients with Phaeo/Para. |
Landmark Studies
1. Importance of Pre-op Blockade
- Historical mortality of surgery was 20-45%. With alpha-blockade preparation, mortality is less than 3%.
2. Lenders et al. (2002)
- Comparison: Plasma vs Urine Metanephrines vs Catecholamines.
- Result: Plasma free metanephrines have highest sensitivity (99%) and specificity.
- Impact: Established plasma metanephrines as first-line test.
What is a Phaeochromocytoma?
It is a rare tumour of the adrenal gland (which sits on top of the kidney). This tumour releases massive amounts of adrenaline.
Symptoms
Because of the adrenaline surges, patients feel sudden attacks of:
- Pounding headache.
- Racing heart.
- Drenching sweat.
- Anxiety or panic (fight-or-flight response).
Is it Cancer?
Usually NO (90% are benign). However, they are dangerous because the high blood pressure can cause strokes or heart attacks.
Treatment
We remove the adrenal gland with keyhole surgery. Crucially, we must prepare you with special blood pressure tablets (Phenoxybenzamine) for 2 weeks before the operation. If we touch the tumour during surgery without these drugs, it squeezes out adrenaline and can stop the heart. You must follow the medication instructions exactly.
Primary Sources
- Lenders JW, et al. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99:1915-1942. PMID: 24893135.
- Neumann HP, et al. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med. 2002;346:1459-1466. PMID: 12000816.
- Lenders JW, et al. Biochemical diagnosis of pheochromocytoma: which test is best?. JAMA. 2002;287:1427-1434. PMID: 11906305.
Common Exam Questions
- Pharmacology: "Why give Phenoxybenzamine before Propranolol?"
- Answer: To prevent unopposed alpha-mediated vasoconstriction which causes hypertensive crisis.
- Genetics: "Phaeo + Thyroid Cancer. Diagnosis?"
- Answer: MEN 2 (RET mutation).
- Surgery: "Most important intra-operative complication?"
- Answer: Hypertensive crisis during tumour manipulation OR Hypotension after removal.
- Medicine: "Diagnostic test of choice?"
- Answer: Plasma Free Metanephrines.
Viva Points
- 10% Rule: Critique it. Familial rate is actually 30-40%.
- Paraganglioma: Extra-adrenal. Often parasympathetic (Head/neck - e.g., Carotid Body/Glomus Jugulare) or Sympathetic (Abdomen).
- MIBG: Mechanism. Analogue of guanethidine/noradrenaline taken up by chromaffin granules.
Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists.